WO2007016201A2 - Formulation d'aryl sulfones non satures ?, ? radioprotecteurs - Google Patents

Formulation d'aryl sulfones non satures ?, ? radioprotecteurs Download PDF

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Publication number
WO2007016201A2
WO2007016201A2 PCT/US2006/029109 US2006029109W WO2007016201A2 WO 2007016201 A2 WO2007016201 A2 WO 2007016201A2 US 2006029109 W US2006029109 W US 2006029109W WO 2007016201 A2 WO2007016201 A2 WO 2007016201A2
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Prior art keywords
composition
compound
group
radioprotective
chlorobenzylsulfone
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PCT/US2006/029109
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WO2007016201A3 (fr
Inventor
Manoj Maniar
Stanley C. Bell
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Traws Pharma Inc
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Onconova Therapeutics Inc
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Priority to NZ565561A priority Critical patent/NZ565561A/en
Priority to CA2617147A priority patent/CA2617147C/fr
Priority to EP06788612A priority patent/EP1909775B1/fr
Priority to US11/989,468 priority patent/US20110028504A1/en
Priority to JP2008524129A priority patent/JP5107246B2/ja
Priority to KR1020087004185A priority patent/KR101309903B1/ko
Application filed by Onconova Therapeutics Inc filed Critical Onconova Therapeutics Inc
Priority to AU2006275822A priority patent/AU2006275822B2/en
Publication of WO2007016201A2 publication Critical patent/WO2007016201A2/fr
Priority to IL189063A priority patent/IL189063A/en
Anticipated expiration legal-status Critical
Publication of WO2007016201A3 publication Critical patent/WO2007016201A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to formulations for pharmacological delivery of cytoprotective agents, e.g., at least one ⁇ , ⁇ unsaturated aryl sulfone, for the protection and/or treatment of cells and tissues from/of the toxicity of ionizing radiation.
  • cytoprotective agents e.g., at least one ⁇ , ⁇ unsaturated aryl sulfone
  • radioprotective gear will not protect normal tissue adjacent a tumor from stray radiation exposure during radiotherapy.
  • Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear.
  • previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful. For example, cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al, Semin. Radiat. Oncol. 3:16-320, 1996), but do not confer systemic protection.
  • the present invention is directed to pharmaceutical compositions for administration for reducing toxic effects of ionizing radiation in a subject, comprising an effective amount of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone, and at least one component selected from the group consisting of a) at least one water soluble polymer in an amount between about 0.5% and about 90% w/v, b) at least one chemically modified cyclodextrin in an amount between about 20% and about 60% w/v, and c) DMA in an amount between about 10% and about 50% w/v.
  • compositions described herein comprise between about 20 mg/ml to about 60 mg/ml of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone, and at least one component selected from the group consisting of a) at least one chemically modified cyclodextrin selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma- cyclodextrin, and hydroxyethyl-beta-cyclodextrin in an amount between about 20% and about 60% w/v, b) a water soluble polymer selected from the group consisting of povidone in an amount between about 0.5% and about 20% w/v and PEG in an amount between about 25% and about 90% w/v, and c) DMA in an amount between about 10% and about 50% w/v, wherein the composition has a pH within the range of about 7.5 to about 9.2.
  • Preferred example pharmaceutical compositions of the present invention comprise between about 30 mg/ml to about 50 mg/ml of the compound ON.1210.Na ((E)-4-Carboxystyryl-4-chlorobenzylsulfone, sodium salt (C ⁇ H 12 ClNaO 4 S)).
  • FIG. IA and IB show the effect of 5 Gy and 10 Gy of ionizing radiation, respectively, on the viability of DU145 prostate tumor cells in the presence or absence of (E)-4-fluorostyryl-4-chlorobenzylsulfone.
  • FIG. 2A and 2B show the effect of 5 Gy and 10 Gy of ionizing radiation, respectively, on the viability of DU 145 prostate tumor cells in the presence or absence of (E)-4-carboxystyryl-4-chlorobenzylsulfone.
  • FIG. 3 A and 3B show the effect of 10 Gy ionizing radiation on the viability of DU145 prostate tumor cells treated post-irradiation, respectively, with (E)-4- fluorostyryl-4-chlorobenzylsulfone and (E)-4-carboxystyryl-4-chlorobenzylsulfone.
  • FIG. 4 is a plot of average body weight (grams) vs. time(days) for C57B6/J mice given 4 mg/kg (E)-4-fluorostyryl-4-chlorobenzylsulfone every other day for 18 days.
  • FIG. 5 is a Kaplan Meyer survival plot of C57B6/J mice pre-treated with (E)-4-carboxystyryl-4-chlorobenzylsulfone at 18 and 6 hrs before receiving 8 Gy of ionizing radiation.
  • FIG. 6 is a Kaplan Meyer survival plot of C57B6/J mice treated with (E)-4- carboxystyryl-4-chlorobenzylsulfone after receiving 8 Gy of ionizing radiation.
  • FIG. 7 shows the structure of the sodium salt of 4-chlorobenzyl-4- carboxystyryl sulfone (ON.1210.Na).
  • FIG. 8 shows a UV Scan of ON.1210.Na in water.
  • FIG. 9 shows representative chromatograms of ON.1210.Na: (a) the mobile phase, (b) standard solution (250 ⁇ g/mL), (c) ON.1210.Na in 0.1N NaOH before autoclaving, and (d) ON.1210.Na in 0.1N NaOH after autoclaving.
  • FIG. 1OA illustrates a mobile phase without ON.1210.Na (Blank).
  • FIG. 1OB shows a representative chromatogram of ON.1210.Na using an isocratic system.
  • FIG. 11 shows pH solubility profiles of ON.1210.Na at ambient temperature.
  • FIG. 12 illustrates degradation of ON.1210.Na as a function of pH at 75 0 C.
  • FIG. 13 shows pseudo first-order rate constant for the degradation of ON.1210.Na as a function of pH at 75 0 C.
  • FIG. 14 shows powder XRPD pattern of ON.1210 free acid.
  • FIG. 15 shows powder XRPD pattern of ON.1210.Na.
  • FIG. 16 shows powder XRPD pattern of ON.1210.Na precipitated from an aquesous solution.
  • the major biological effects of radiation exposure are the destruction of bone marrow cells, gastrointestinal (GI) damage, lung pneumonitis, and central nervous system (CNS) damage.
  • GI gastrointestinal
  • CNS central nervous system
  • the long-term effects of radiation exposure include an increase in cancer rates. It has been estimated that the exposure of 100 rems (roentgen equivalent man: a measurement used to quantify the amount of radiation that would produce harmful biological effects) would produce ARS symptoms. Exposure levels above 300 rems would result in the death of approximately 50% of the exposed population.
  • the ⁇ , ⁇ -unsaturated aryl sulfones provide significant and selective systemic protection of normal cells from radiation- induced damage in animals. When used in radiotherapy techniques, these compounds also exhibit independent toxicity to cancer cells.
  • Compositions and formulations of ⁇ , ⁇ unsaturated aryl sulfones described herein protect normal cells and tissues from the effects of acute and chronic exposure to ionizing radiation.
  • the ⁇ , ⁇ unsaturated aryl sulfones are also operationally cytotoxic in tumor cells.
  • compositions described herein are intended for prophylactic use, for example, to enhance survival in personnel who are in imminent danger of exposure to life- threatening levels of x-ray or gamma radiation, and/or to enhance survival in personnel who have just received life-threatening levels of xray or gamma radiation.
  • pre-treatment with ON.01210.Na for example, by the intravenous, sub-cutaneous or intraperitoneal route resulted in protection of mice from a lethal dose of ionizing radiation.
  • Subjects may be exposed to ionizing radiation when undergoing therapeutic irradiation for the treatment of proliferative disorders.
  • Such disorders include cancerous and non-cancer proliferative disorders.
  • Formulations described herein are effective in protecting normal cells during therapeutic irradiation of a broad range of tumor types, including but not limited to the following: breast, prostate, ovarian, lung, colorectal, brain (i.e., glioma) and renal.
  • the compositions are also effective against leukemic cells, for example.
  • compositions are useful in protecting normal cells during therapeutic irradiation of abnormal tissues in non-cancer proliferative disorders, including but not limited to hemangiomatosis in new born, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget' s Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
  • non-cancer proliferative disorders including but not limited to hemangiomatosis in new born, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget' s Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
  • Therapeutic ionizing radiation may be administered to a subject on any schedule and in any dose consistent with the prescribed course of treatment, as long as the ⁇ , ⁇ unsaturated aryl sulfone radioprotectant compound is administered prior to the radiation.
  • the course of treatment differs from subject to subject, and those of ordinary skill in the art can readily determine the appropriate dose and schedule of therapeutic radiation in a given clinical situation.
  • Compositions of ⁇ , ⁇ unsaturated aryl sulfones described herein should be administered far enough in advance of the therapeutic radiation such that the compound is able to reach the normal cells of the subject in sufficient concentration to exert a radioprotective effect on the normal cells.
  • At least one ⁇ , ⁇ unsaturated aryl sulfone may be administered as much as about 24 hours, preferably no more than about 18 hours, prior to administration of the radiation.
  • an ⁇ , ⁇ unsaturated aryl sulfone formulation is administered at least about 6 - 12 hours before administration of the therapeutic radiation.
  • the ⁇ , ⁇ unsaturated aryl sulfone is administered once at about 18 hours and again at about 6 hours before the radiation exposure.
  • One or more ⁇ , ⁇ unsaturated aryl sulfones may be administered simultaneously, or different ⁇ , ⁇ unsaturated aryl sulfones may be administered at different times during the treatment.
  • an about 24 hour period separates administration of ⁇ , ⁇ unsaturated aryl sulfone and the therapeutic radiation. More preferably, the administration of ⁇ , ⁇ unsaturated aryl sulfone and the therapeutic radiation is separated by about 6 to 18 hours. This strategy will yield significant reduction in radiation-induced side effects without affecting the anticancer activity of the therapeutic radiation.
  • An acute dose of ionizing radiation which may cause remediable radiation damage includes a localized or whole body dose, for example, between about 10,000 millirem (0.1 Gy) and about 1,000,000 millirem (10 Gy) in 24 hours or less, preferably between about 25,000 millirem (0.25 Gy) and about 200,000 (2 Gy) in 24 hours or less, and more preferably between about 100,000 millirem (1 Gy) and about 150,000 millirem (1.5 Gy) in 24 hours or less.
  • a chronic dose of ionizing radiation which may cause remediable radiation damage includes a whole body dose of about 100 millirem (.001 Gy) to about 10,000 millirem (0.1 Gy), preferably a dose between about 1000 millirem (.01 Gy) and about 5000 millirem (.05 Gy) over a period greater than 24 hours, or a localized dose of 15,000 millirem (0.15 Gy) to 50,000 millirem (0.5 Gy) over a period greater than 24 hours.
  • radioprotective compositions described herein should provide protection when administered just after, e.g., up to about four hours after, exposure.
  • ⁇ , ⁇ unsaturated aryl sulfone as used herein is meant a chemical compound containing one or more ⁇ , ⁇ unsaturated aryl sulfone groups:
  • ⁇ -O 2 S-HC HC-Q 2 ⁇ a ⁇
  • Q 2 is substituted or unsubstituted aryl, and the hydrogen atoms attached to the ⁇ and ⁇ carbons are optionally replaced by other chemical groups.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to a ring atom.
  • the degree of substitution in a ring system may be mono-, di-, tri- or higher substitution.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner or may be fused. Examples include phenyl; anthracyl; and naphthyl, particularly 1-naphthyl and 2-naphthyl. The aforementioned listing of aryl moieties is intended to be representative, not limiting. It is understood that the term “aryl” is not limited to ring systems with six members.
  • heteroaryl by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic aromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure.
  • heteroaryls examples include benzimidazolyl, particularly 2- benzimidazolyl; benzofuryl, particularly 3-, A-, 5-, 6- and 7-benzofuryl; 2- benzothiazolyl and 5-benzothiazolyl; benzothienyl, particularly 3-, A-, 5-, 6-, and 7- benzothienyl; 4-(2-benzyloxazolyl); furyl, particularly 2- and 3-furyl; isoquinolyl, particularly 1- and 5 -isoquinolyl; isoxazolyl, particularly 3-, 4- and 5-isoxazolyl; imidazolyl, particularly 2-, -4 and 5-imidazolyl; indolyl, particularly 3-, A-, 5-, 6- and 7-indolyl; oxazolyl, particularly 2-, 4- and 5-oxazolyl; purinyl; pyrrolyl, particularly 2-pyrrolyl, 3-pyrrolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; pyra
  • the ⁇ , ⁇ unsaturated aryl sulfone group is a styryl sulfone group:
  • styryl sulfone or “styryl sulfone compound” or “styryl sulfone therapeutic” as used herein is meant a chemical compound containing one or more such styryl sulfone groups.
  • ⁇ , ⁇ unsaturated aryl sulfone radioprotective compounds are characterized by cis-trans isomerism resulting from the presence of a double bond. Stearic relations around a double bond are designated as "Z" or "E”. Both configurations are included in the scope of " ⁇ , ⁇ unsaturated aryl sulfone":
  • the ⁇ , ⁇ unsaturated aryl sulfone compound is a compound of the formula I:
  • n is one or zero
  • Q 1 and Q 2 are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • n in formula I is one, that is, the compounds comprise ⁇ , ⁇ unsaturated benzylsulfones, e.g. styryl benzylsulfones.
  • Q 1 and/or Q 2 are selected from substituted and unsubstituted heteroaryl; for example, (E)-3- furanethenyl-2,4-dichlorobenzylsulfone.
  • Q 1 and Q 2 are selected from substituted and unsubstituted phenyl.
  • Preferred compounds where Q 1 and Q 2 are selected from substituted and unsubstituted phenyl comprise compounds of the formula II:
  • Q i a and Q 2a are independently selected from the group consisting of phenyl and mono-, di-, tri-, terra- and penta-substituted phenyl where the substituents, which may be the same or different, are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl.
  • compounds of formula II are at least di-substituted on at least one ring, that is, at least two substituents on at least one ring are other than hydrogen. In another embodiment, compounds of formula II are at least trisubstituted on at least one ring, that is, at least three substituents on at least one ring are other than hydrogen.
  • the radioprotective compound has the formula III:
  • Ri, R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluororaethyl.
  • the radioprotective compound is according to formula III, and R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, cyano, and trifluoromethyl; and R 3 and R 4 are independently selected from the group consisting of hydrogen and halogen.
  • the radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound is a compound of the formula Ilia, wherein R 2 and R 4 are other than hydrogen:
  • Preferred compounds according to formula Ilia having the E-configuration include, but are not limited to, (E)-4-fluorostyryl-4-chlorobenzylsulfone; (E)-4- chlorostyryl-4-chlorobenzylsulfone; (E)-2-chloro-4-fluorostyryl-4- chlorobenzylsulfone; (E)-4-carboxystyryl-4-chlorobenzyl sulfone; (E)-4- fluorostyryl-2,4-dichlorobenzylsulfone; (E)-4-fluorostyryl-4-bromobenzylsulfone; (E)-4-chlorostyryl-4-bromobenzylsulfone; (E)-4-bromostyryl-4- chlorobenzylsulfone; (E)-4-fluorostyryl-4-trifluoromethylbenzylsulfone; (E)-4- fluorostyryl-3,4-d
  • compounds of formula Ilia have the Z configuration wherein Ri and R 3 are hydrogen, and R 2 and R 4 are selected from the group consisting of 4-halogen.
  • Such compounds include, for example, (Z)-4- chlorostyryl-4-chlorobenzylsulfone; (Z)-4-chlorostyryl-4-fluorobenzylsulfone; (Z)- 4-fluorostyryl-4-chlorobenzylsulfone; (Z)-4-bromostyryl-4-chlorobenzylsulfone; and (Z)-4-bromostyryl-4-fluorobenzylsulfone.
  • the radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound is a compound of the formula IV:
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, Cl -8 alkyl, C 1-8 alkoxy, nitro, cyano, carboxy, hydroxy, and trifluoromethyl.
  • R 1 in formula IV is selected from the group consisting of hydrogen, chlorine, fluorine and bromine; and R 2 , R 3 and R 4 are hydrogen.
  • a preferred compound of formula IV is (Z)-styryl-(E)-2-methoxy-4- ethoxystyrylsulfone.
  • the radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound is a compound of the formula V:
  • Q 3 , Q 4 and Q 5 are independently selected from the group consisting of phenyl and mono-, di-, tri-, tetra- and penta-substituted phenyl where the substituents, which may be the same or different, are independently selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C 1 -C6 trifluoroalkoxy and trifluoromethyl.
  • the radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound is a compound of the formula Va:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, Cl-8 alkoxy, nitro, cyano, carboxyl, hydroxyl, and ttifluoromethyl; and R 3 is selected from the group consisting of unsubstituted phenyl, mono- substituted phenyl and di-substituted phenyl, the substituents on the phenyl ring being independently selected from the group consisting of halogen and Cl-8 alkyl.
  • R 1 in formula Va is selected from the group consisting of fluorine and bromine; R 2 is hydrogen; and R 3 is selected from the group consisting of 2- chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, and 2-nitrophenyl.
  • a preferred radioprotective styryl sulfone according to formula Va is the compound wherein R 1 is fluorine, R 2 is hydrogen and R 3 is phenyl, that is, the compound 2-(phenylsulfonyl)-l-phenyl-3-(4-fluorophenyl)-2-propen-l-one.
  • dimethylamino(C2-C6 alkoxy) is meant (CH 3 ) 2 N(CH 2 ) n O- wherein n is from 2 to 6.
  • n is 2 or 3.
  • n is 2, that is, the group is the dimethylaminoethoxy group, that is, (CHs) 2 NCH 2 CH 2 O-.
  • phosphonato is meant the group -PO(OH) 2 .
  • sulfamyl is meant the group -SO 2 NH 2 .
  • the carbon chain may be branched or straight, with straight being preferred.
  • the alkoxy groups comprise C1-C6 alkoxy, more preferably C1-C4 alkoxy, most preferably methoxy.
  • (E)- ⁇ , ⁇ unsaturated aryl sulfones may be prepared by Knoevenagel condensation of aromatic aldehydes with benzylsulfonyl acetic acids or arylsulfonyl acetic acids. The procedure is described by Reddy et ah, Acta. Chim. Hung. 115:269-71 (1984); Reddy et al, Sulfur Letters 13:83-90 (1991); Reddy et al, Synthesis No. 4, 322-23 (1984); and Reddy et al, Sulfur Letters 7:43-48 (1987), the entire disclosures of which are incorporated herein by reference. See, particularly, the entire disclosures of U.S. Patent Nos.
  • the ⁇ , ⁇ unsaturated aryl sulfones may take the form or pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically- acceptable.
  • Q 1 and Q 2 are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl illustrated by Table 2 below.
  • ON.1210.Na is a derivative of chlorobenzylsulfone.
  • This and related compounds are described herein as exhibiting valuable prophylactic properties which mitigate the effects of accidental and intentional exposure to life-threatening levels of irradiation. Hence, a systematic development of this and related compounds is described with the objective of developing a shelf stable formulations.
  • Table 4 describes the general physical properties of ON.1210.Na.
  • the example compound is a sodium salt of (E)-4-Carboxystyryl-4-chlorobenzylsulfone.
  • the compound ON 01210.Na appears to form at least one polymorph.
  • X-ray diffraction pattern, for example, of precipitated ON 01210.Na is different from that of the originally synthesized compound.
  • Polymorphs of ON 01210.Na are intended to be within the scope of the claims appended hereto.
  • Treatment of normal human fibroblasts with ON 01210.Na, for example, prior to exposure to cytotoxic levels of ionizing radiation provides dose-dependent radio-protection.
  • the physio-chemical properties of ON.1210.Na was determined in order to evaluate appropriate formulation approaches for development of a safe, reliable and effective parenteral formulation of these compounds. This includes microscopic studies, partition coefficient, pKa, pH solubility studies, pH stability studies under accelerated conditions, solid state characterization of the drug substance, and solid state stability of drug substance under accelerated conditions. See, section IV, infra.
  • This example compound has a low octanol:water partition coefficient (1.28-2.87).
  • the equilibrium solubility of the drug at pH 4.0, 5.0, 6.0, 7.4, 8.0, 9.0 was 0.000154, 0.0379, 0.715, 11.09, 16.81, 23.3 mg/mL, respectively.
  • the pKa calculated from pH-solubility studies was 2.85 ⁇ 0.6.
  • the pH-stability profile of the drug indicated better stability at neutral and biological pH but degradation was rapid under acidic conditions. The degradation followed a pseudo-first-order rate.
  • the accelerated solid-state stability study of the bulk drug substance showed no evidence of degradation.
  • This drug is quite stable in an aqueous environment at biological pH. Therefore, it can be formulated as a shelf stable parenteral formulation.
  • the aqueous solubility of the drug as the free acid is low and can be significantly enhanced by increase in pH, co-solvents and complexation.
  • compositions described and contempated herein are not so limited, due to the oral, for example, bioavailability of the compounds upon administration, a preferred route of administration of the compositions described herein include, for example, parenteral administration.
  • Parenteral administration includes intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., into the bladder), intradermal, topical or subcutaneous administration.
  • the ⁇ , ⁇ unsaturated aryl sulfone may be administered in the form of a pharmaceutical composition comprising one or more ⁇ , ⁇ unsaturated aryl sulfones in combination with a pharmaceutically acceptable carrier.
  • the ⁇ , ⁇ unsaturated aryl sulfone in such formulations may comprise from 0.1 to 99.99 weight percent.
  • pharmaceutically acceptable carrier any carrier, diluent or excipient which is compatible with the other ingredients of the formulation and is not deleterious to the subject.
  • the specific dose and schedule of ⁇ , ⁇ unsaturated aryl sulfone to obtain the radioprotective benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient, the nature and stage of the disease being treated, the aggressiveness of the disease, and the route of administration, and the specific toxicity of the radiation.
  • a daily dosage of from about 0.01 to about 150 mg/kg/day may be utilized, more preferably from about 0.05 to about 50 mg/kg/day.
  • Particularly preferred are doses from about 1.0 to about 10.0 mg/kg/day, for example, a dose of about 7.0 mg/kg/day.
  • the dose may be given over multiple administrations, for example, two administrations of 3.5 mg/kg. Higher or lower doses are also contemplated.
  • the ⁇ , ⁇ unsaturated aryl sulfones may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, cyclodextrins or a glycol such as propylene glycol or polyethylene glycol as described infra.
  • a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, cyclodextrins or a glycol such as propylene glycol or polyethylene glycol as described infra.
  • Solutions for parenteral administration preferably contain a pharmaceutically acceptable, water soluble salt of the ⁇ , ⁇ unsaturated aryl sulfone.
  • Stabilizing agents, antioxidizing agents, chelating agents, and preservatives, for example, may also be added.
  • Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA as a chelator, for example.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
  • shelf-stable pharmaceutical compositions which comprise effective amount of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound are described herein.
  • effective amount of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound, for example, as used herein refers to an amount of compound, after dilution as described infra, that is effective to mitigate, reduce or eliminate toxicity associated with radiation in normal cells of the subject and/or to impart a direct cytotoxic effect to abnormally proliferating cells in the subject.
  • an effective amount of the radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound refers to an amount of at least one ⁇ , ⁇ unsaturated aryl sulfone effective to reduce or eliminate the toxicity associated with radiation in bone marrow removed from a subject and/or to impart a direct cytotoxic effect to malignant cells in the bone marrow removed from the subject.
  • Each ⁇ , ⁇ unsaturated arylsulfone is administered, for example, in a concentration of about 0.25 micromolar to about 100 micromolar; preferably, from about 1.0 to about 50 micromolar; more preferably from about 2.0 to about 25 micromolar. Particularly preferred concentrations for administration are, for example, about 0.5, 1.0 and 2.5 micromolar and about 5, 10 and 20 micromolar. Higher or lower concentrations may also be used depending upon factors well known in the art.
  • compositions of the present invention are generally formulated with active ingredient, e.g., one or more compounds described herein, in a concentrated form for storage and handling prior to dilution with suitable parenteral diluent prior to infusion.
  • Preferred shelf-stable compositions of the present invention for dilution prior to administration, generally comprise between about 10 mg/ml to about 90 mg/ml of at least one ⁇ , ⁇ unsaturated aryl sulfone.
  • Preferred compositions of the present invention comprise between about 20 mg/ml to about 80 mg/ml of at least one ⁇ , ⁇ unsaturated aryl sulfone.
  • Example compositions of the present invention comprise between about 30 mg/ml to about 50 mg/ml (e.g., about 40mg/ml) of at least one ⁇ , ⁇ unsaturated aryl sulfone (e.g., (E)-4-carboxystyryl-4-chlorobenzylsulfone sodium salt (ON.1210.Na)); wherein the composition exhibits a pH within the range of about 7.2 to about 9.2.
  • ⁇ , ⁇ unsaturated aryl sulfone e.g., (E)-4-carboxystyryl-4-chlorobenzylsulfone sodium salt (ON.1210.Na)
  • a single dosage is generally within the range of about 1 ml to about 5 ml of any of the compositions described herein.
  • Individual 3 ml dosages of compositions described herein are contemplated, for example.
  • the dosages may be packaged, for example, in 5 ml vials.
  • Compositions of the present invention may, for example, be diluted with about 7 parts diluent (7: 1) prior to administration. However, the dilution factor and the diluent employed depend on the concentration of drug in the formulation. Compositions of the present invention, however, may be diluted with anywhere, for example, within the range of about 2 volumes of suitable parenteral diluent prior to infusion to about 12 volumes of suitable parenteral diluent, prior to infusion.
  • the final diluted product for parenteral administration of compositions of the present invention should have a pH within the range of about 6.5 to about 10.0.
  • the final diluted product for parenteral administration should have a pH within the range of about 7.0 to about 9.5
  • a diluted product pH of about 7.0 to about 8.0 is preferred.
  • the osmolality of the diluted formulation for administration should be approximately within the range of about 200 to about 400 mOsm/kg.
  • Preferred osmolarity of the diluted formulation for administration should be approximately within the range of about 270 to about 330 mOsm/kg.
  • a preferred osmolarity of the diluted formulation for administration should be approximately 300 mOsm/kg.
  • compositions described herein are preferrably aqueous-based; however, ethanol, for example, is also a preferred base-component of the formulations described herein.
  • DMA N,N-dimethylacetamide
  • compositions described herein are particularly contemplated that comprise between about 15% and about 40% by weight of DMA.
  • Composition for parenteral administration comprising an effective amount of a compound described herein and about 20% to about 35% by weight of DMA are example preferred embodiments.
  • An example composition of the present invention comprises an effective amount of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound in a formulation wherein components DMA:WATER;ETHANOL exist in an approximate 1:1:1 ratio, for example.
  • composition of the present invention comprises an effective amount of at least one radioprotective ⁇ , ⁇ unsaturated aryl sulfone compound in a formulation wherein components DM A: W ATER: and PEG400, for example, (at least one water soluble polymer (WSP)) exist in an approximate 1:2:2 ratio, for example.
  • WSP water soluble polymer
  • DMA:WATER:WSP water soluble polymer
  • the 'water soluble polymer' component can be much greater, e.g., as described infra, in many embodiments at least about 40% by weight of at least one water soluble polymer.
  • compositions for parenteral administration comprising an effective amount of a compound described herein and at least about 0.5% by weight of at least one water soluble polymer is provided.
  • Formulations of the present invention are preferred which have a pH within the range of about 6.8 to about 9.6.
  • Formulations described herein are preferred which have a pH within a range of about 7.5 to about 9.2.
  • Compositions are preferred that comprise between about 5% and about 90% of at least one water soluble polymer, e.g.
  • water soluble polymer includes but is not limited to water soluble polymer excipients known in the art including polyethylene glycol (PEG), polypropylene glycol, poly-oxyethylene, poly-oxyethylene-poly-oxypropylene copolymer, polyglycerol, polyvinylalcohol, polyvinylpyrrolidone (PVP) (Povidone (soluble homopolymer of N-vinyL-2-pyrrolidone)), polyvinylpyridine N-oxide, copolymer of vinylpyridine N-oxide and vinylpyridine, and the like, as well as derivatives thereof, and combinations thereof.
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidone
  • Povidone soluble homopolymer of N-vinyL-2-pyrrolidone
  • Poly-oxyethylene and/or poly-oxyethylene-poly-oxypropylene copolymers are example water-soluble polymers for use in formulations of the present invention.
  • Poloxamer 407 e.g., Pluronic F 127, L ⁇ trol® micro 127
  • Poloxamer 188 e.g., Pluronic F 68, L ⁇ trol® micro 68
  • Pluronic F 68, L ⁇ trol® micro 68 are poly-oxyethylene-poly- oxypropylene copolymers that can be used independently or in combination in formulations of the present invention.
  • BASF Corporation Mount Olive, NJ.
  • Polyethylene glycols (PEGs) are preferred water soluble polymers.
  • Low molecular weight liquid polyethylene glycols for example, PEG 300, PEG 400, PEG 600, and PEG 800, are preferred water soluble polymers that can be used independently or in combination with each other, for example, in formulations of the present invention. Particularly preferred are PEG 300, PEG 400, and PEG 600. Lutrol® E 300, Lutrol® E 400 and Lutrol® E 600, for example, are commercially available from BASF Corporation, Mount Olive, NJ. PEG 400 (Polyethylene glycol 400, Macrogol 400, PEG 400, Poly(oxy-l,2-ethanediyl),alpha-hydro-omega- hydroxy- (CAS No: 25322-68-3)), e.g., Lutrol® E 400. is preferred.
  • Example water soluble polymers selected from the group consisting essentially of PEG 300, PEG 400, PEG 600, and PEG 800 are preferred. Although not specifically listed here PEG products substantially the same, otherwise within this characteristic range of PEG entities, may be employed in compositions of the present invention.
  • Low molecular weight povidone grades (CAS No: 9003-39-8), Kollidon® 12 PF and Kollidon® 17 PF, for example, form a soluble complex between the compounds and povidone. Both products are available as pyrogen-free powders, suitable for use in injectables, from BASF Corporation, Mount Olive, NJ.
  • compositions of the present invention are exemplified herein that comprise Povidone K 90, for example, at concentrations of about 1% to about 5% in water. These compositions are further contemplated, for example, that comprise Povidone K 90, for example, at concentrations of about 0.5% to about 10% in water. Low molecular weight Povidones, for example, may be employed at much higher concentrations in compositions of the present invention, e.g., between about 5% by weight and about 40%. A preferred range is between about 5% to about 20% by weight, depending on the viscosity of the formulation.
  • Cyclodextrins are preferred components of compositions described herein. Cyclodextrin drug compositions described herein are easily diluted, for example, eliminating the need for elaborate mixing procedures. Chemically modified cyclodextrin, hydroxypropyl-b-cyclodextrin, for example, formulations are preferred for parenteral administration due to the ability to of the cyclodextrins to solubilize and stabilize the compounds described herein as well as the superior safety profile exhibited by the chemically modified cyclodextrins.
  • cyclodextrins referred to herein can reduce dosing volume and in situ irritation resulting from high pH, for example, other solvents, or any direct chemical irritancy due to the compounds otherwise described herein.
  • Many different chemical moieties may be introduced into the Cyclodextrin molecule by reaction with the hydroxyl groups lining the upper and lower ridges of the toroid; for example, hydroxypropyl, carboxymethyl, and acetyl. Since each Cyclodextrin hydroxyl groups differs in its chemical reactivity, reaction processes produces an amorphous mixture of thousands of positional and optical isomers.
  • Cyclodextrin molecules (alpha, beta, or gamma) can have up to 3(n) substituents, where n is the number of glucopyranose units of the Cyclodextrin molecule. This is referred to as the degree of substitution (DS).
  • the DS refers to substituents other than hydrogen; substituents may be all of one kind or mixed.
  • HPCD Hydroxypropyl-B-Cyclodextrin
  • hydroxypropyl cyclodextrin is itself very soluble in water (greater than 500 mg/ml at room temperature).
  • Dr. Joseph Pitha of the NIH has experimentally evaluated many of the uses of this cyclodextrin derivative and found that it can be conveniently applied to cell cultures and membrane preparations. It is also observed that HPCD is non-toxic after IP and IV administration to different rodent species. The maximum human dose of HPCD given parenterally was approximately 500 mg/kg iv given continuously as a 5 percent aqueous solution to one individual for four days; no adverse clinical effects were reported.
  • compositions which generally comprise an effective amount of at least one ⁇ , ⁇ unsaturated aryl sulfone, water, and at least one chemically modified cyclodextrin.
  • Embodiments of formulations of the present invention are preferred which comprise about 5% to about 90% w/v chemically modified cyclodextrin(s) and have a pH within the range of about 6.8 to about 9.6.
  • Formulations described herein are preferred which have a pH within a range of about 7.6 to about 9.2. High pH, e.g., about 8 to about 9, or higher, is preferred.
  • Particularly preferred compositions for the present invention comprise about 20% to about 60% w/v chemically modified cyclodextrin(s).
  • compositions for the present invention comprise about 30% to about 50% w/v chemically modified cyclodextrin(s).
  • An example composition of the present invention comprises at least one chemically modified cyclodextrin selected from the group consisting of 2-hydroxypropyl-beta-Cyclodextrin, 2-hydroxypropyl-gamma- Cyclodextrin, and hydroxyethyl-beta-Cyclodextrin, preferably in an amount of about 30% to about 50% w/v, an effective amount of at least one ⁇ , ⁇ unsaturated aryl sulfone, e.g., (E)-4-carboxystyryl-4-chlorobenzylsulfone sodium salt (ON.1210.Na), and water.
  • 2-hydroxypro ⁇ yl-beta-Cyclodextrin (Hydroxypropyl-B-Cyclodextrin) (hydroxypropyl cyclodextrin) (HPCD) is a preferred chemically modified cyclodextrin for use in compositions of the present invention.
  • shelf-stable aqueous compositions for the present invention for dilution prior to parenteral administration for the protection of normal cells from toxicity of ionizing radiation or to mitigate the effects of accidental/intentional exposure to life-threatening levels of irradiation, comprise, for example, an effective amount of at least one ⁇ , ⁇ unsaturated aryl sulfone, and about 35% to about 45% (e.g., about 40% w/v) w/v chemically modified cyclodextrin.
  • Preferred shelf-stable compositions of the present invention for dilution prior to administration, comprise between about 10 mg/ml to about 90 mg/ml of at least one ⁇ , ⁇ unsaturated aryl sulfone and at least one chemically modified cyclodextrin.
  • Particularly preferred compositions of the present invention comprise between about 20 mg/ml to about 80 mg/ml of at least one ⁇ , ⁇ unsaturated aryl sulfone.
  • Example compositions of the present invention comprise between about 30 mg/ml to about 50 mg/ml (e.g., about 40mg/ml) of at least one ⁇ , ⁇ unsaturated aryl sulfone (e.g., (E)-4-carboxystyryl-4-chlorobenzylsulfone sodium salt (ON.1210.Na)); and, about 30% to about 50% w/v (e.g., about 40%) chemically modified cyclodextrin (e.g., hydroxypropyl cyclodextrin); wherein the composition has a pH within the range of about 7.6 to about 8.5 (e.g., about 7.9).
  • ⁇ unsaturated aryl sulfone e.g., (E)-4-carboxystyryl-4-chlorobenzylsulfone sodium salt (ON.1210.Na)
  • chemically modified cyclodextrin e.g., hydroxypropyl
  • Preferred formulations described and claimed herein have significantly increased the solubility of radioprotective ⁇ , ⁇ unsaturated aryl sulfones, ON.1210.Na, for example, to allow concentrated formulations of the present invention, wherein upon dilution, the drug is physically stable for at least about 24 hours.
  • ON.1210.Na a sodium salt of a chlorobenzylsulphone, is an example of an efficacious radiation protectant drug.
  • ON.1210.Na is particularly shown to protect during life-threatening levels of radiation exposure. Described herein are shelf stable parenteral formulations of this and related compounds for therapeutic administration to patients.
  • a stability indicating HPLC assay is used during the preformulation studies.
  • Preformulation studies include determination of microscopic and macroscopic properties, partition coefficient, pKa, pH-solubility, pH-stability, solid-state characterization and solid-state stability.
  • XRD and thermal analyses re used to characterize the solid and solid-state stability.
  • the solid-state stability as well as the pH stability of the drug is carried out at 75 0 C.
  • Microscopic and XRD data reveals that the drug is crystalline having an irregular plate like crystals.
  • the drug has a low octanol:water partition coefficient (1.28-2.87).
  • the equilibrium solubility of the drug at pH 4.0, 5.0, 6.0, 7.4, 8.0, 9.0 is 0.000154, 0.0379, 0.715, 11.09, 16.81, 23.3 mg/niL, respectively.
  • the pKa calculated from a pH-solubility study is 2.85 ⁇ 0.6.
  • the pH-stability profile of the drug indicates better stability at neutral and biological pH but degradation is rapid under acidic condition. The degradation followed a first-order rate. The accelerated solid-state stability of the bulk drug substance shows no evidence of degradation.
  • the solubility of the drug can be significantly increased with increase in pH. Also, the stability of the drug can be enhanced by buffering the aqueous solutions around pH 7. The drug is quite stable in an aqueous environment rendering itself for the development of a shelf stable formulation.
  • the isocratic system uses a mobile phase consisting of Acetonitrile:0.1% Trifluoroacetic acid in water (60:40 v:v) at a flow rate of 1 mL/min.
  • a C- 18 Gemini column 250 x 4.6 mm is used and effluents are monitored at a 254 nm. Forced degradation is carried out by exposing ON.1210.Na to 0.1N HCl, 0.1N NaOH and 3% (v/v) hydrogen peroxide.
  • the validation parameters include linearity, specificity, sensitivity, precision and accuracy.
  • Standard curves are linear in the concentration range of 0-500 ⁇ g/mL. The retention times of the drug and several degradation products were well within seven minutes.
  • the Relative Standard Deviation (RSD) values for the within-day and day- to-day precision range from 0.4 to 2.5 % and 2.2 to 4.4 %, respectively.
  • the RSD for accuracy measurement ranges from 0.85 to 1.7%.
  • the critical level, the detection level and the determination level for this assay are 2.86 ⁇ 0.67 ⁇ g/mL, 5.69 ⁇ 0.67 ⁇ g/mL and 15.6 ⁇ 1.79 ⁇ g/mL, respectively.
  • the first step in this process is the development of a stability indicating HPLC assay.
  • the next phase is the validation of the assay.
  • This HPLC assay is able to support preformulation, formulation development, and the stability studies of the bulk drug and formulated ON.1210.Na, for example. Described herein is the development of the stability indicating assay, and the validation. The suitability of the assay is demonstrated by performing forced degradation studies on the bulk drug substance in solid state, and under acidic, alkaline, oxidizing and autoclaving conditions.
  • HPLC assay A sensitive, highly specific and accurate stability indicating HPLC assay is developed and validated for the analysis of ON.1210.Na in aqueous samples.
  • the following is a list of materials and equipment used to perform the method development and validation.
  • Trifluoroacetic Acid (Sigma, St. Louis, MO, USA); Acetonitrile, water
  • UV scan of ON.1210.Na is obtained with a lO ⁇ g/mL of solution of ON.1210.Na in water using a UV 1700 PHARMASPEC model spectrophotometer (Shimadzu, Japan).
  • the UV scan is shown in Figure 8.
  • the UV spectrum shows two distinct maxima.
  • the ⁇ ma ⁇ for ON.1210.Na in this solvent is found to be at 281 nm and the second maxima occurs at 216 nm.
  • the initial HPLC method development process utilizes a gradient system with the following mobile phase composition:
  • the gradient used is a linear gradient from 0% B to 100% B over 30 minutes.
  • a photodiode array detector (model SPD-MlOAVP) is used at 3 wavelengths 230, 254 and 320 nm for monitoring the eluent. These three wavelengths are selected because of past experience with a similar analog ON.1910.
  • the column used is a C- 18 Gemini column (Phenomenex, CA).
  • the flow rate is 1.0 mL/min.
  • the resulting retention time of ON.1210.Na is approximately 23 minutes. Based on the data, this system is considered suitable for the detection of the parent compound with the other impurities present in the compound.
  • Representative chromatograms of ON.1210.Na obtained at 254 nm is shown in Figure 9 (a-d). The chromatograms are presented in descending order.
  • the gradient system indicates that the retention time of the drug is more than 20 minutes and the degradation products during a forced degradation with 0.1N NaOH can be well separated and detected using the reversed phase system. Optimization of the mobile phase composition for the isocratic system is then undertaken.
  • the next objective of the method development process is to reduce the run time without sacrificing the resolution between ON.1210.Na and its impurities/degradation products.
  • the efforts are focused on developing an isocratic system utilizing the various combinations of acidified water and acetonitrile as the mobile phase.
  • Three mobile phase composition are selected. They are: 20:80; 40:60 and 60:40 (v/v) of acetonitrile:water containing 0.1% TFA.
  • the retention time of ON.1210.Na in the first two mobile phase compositions are more than 8 minutes, whereas with 60:40 (ACN:water) composition, the retention time is approximately 5 minutes at a flow rate of 1 mL/min.
  • the resolution between ON.1210.Na and its three minor impurities is also good.
  • a representative chromatogram is shown in Figure 10.
  • the current lot (ON062604- 121 ONa) of ON.1210.Na shows a HPLC purity of more than 99%, with three other major impurities eluting at the retention times of 4.0, 6.0 and 6.6 minutes. Therefore, the third mobile phase composition is selected for further evaluation.
  • the ON.1210.Na sample is prepared in HPLC grade water at a concentration of 200 ⁇ g/mL. All the peaks detected in the chromatogram at time zero are noted with their corresponding retention time and absolute peak areas. The solution is crimped into a 5mL glass vial and autoclaved. After autoclaving, the sample is filtered through a 0.1 ⁇ filter and 20 ⁇ L of the filtered sample is analyzed. The absolute peak area of the peak after autoclaving and appearance of any additional peaks due to possible degradation is shown in Table 9. Table 9: Effect of Autoclave on Aqueous Solution of ON.1210.Na
  • the results indicate no reduction in the Area Under the Curve (AUC) of the parent peak, and also no additional peaks are detected. Based on this observation, it seems that the bulk drug ON.1210.Na is stable under the autoclaving conditions.
  • the stock standard solution (1000 ⁇ g/ml) is prepared by dissolving 0.10 g of ON.1210.Na in 100ml 60:40 (v/v) of ACN:water without TFA. The apparent pH of the solution before addition of the drug is 7.52.
  • Various standard solutions (20-500 ⁇ g ml "1 ) are then prepared by diluting the above stock solution with mobile phase without TFA to yield nominal concentrations over a range 10-500 ⁇ g/ml as shown in the table below.
  • Table 13 Preparation of Standard Solutions
  • Three quality control samples are also prepared from the same stock solution (1000 ⁇ g /ml) for the accuracy measurement as shown in table below.
  • the standard solution or the sample to be analyzed (200 ⁇ l) is placed in sample vial in an auto injector and an aliquot (20 ⁇ l) is analyzed by HPLC.
  • the mobile phase is prepared by mixing 600 ml of acetonitrile and 400 ml of
  • the critical level is defined as the assay response above which an observed response is reliably recognized as detectable.
  • the critical level is 2.86 + 0.33 ⁇ g ml "1 (Mean ⁇ S.D.).
  • the detection level is the actual net response, which may a priori be expected to lead to detection. This is the lowest better value of the true concentration that is "nearly sure” to produce a measured value that results in detection.
  • the detection level is
  • the determination level is the concentration at which the measurement precision will be satisfactory for quantitative determination.
  • the determination level is 15.6 ⁇ 1.79 ⁇ g ml "1 (Mean + S. D.) for a level of precision of 10% RSD.
  • the standard solutions are very stable over a period of 12 days when kept at room temperature.
  • the RSD (less than 2.5%) of the slope of the standard curves for the day-to-day precision measurement over 12 day's storage data supports the claim. No additional peaks are detected in the standards when kept over 12 days at room temperature.
  • the octanol-water partition coefficient of the drug is determined at 25 0 C. Equal volumes (10 ml) saturated solution of ON.1210.Na in n-octanol and HPLC water are equilibrated at 25 0 C in a shaking water bath for 48 hours. The pH of the aqueous phase is also determined. At a predetermined time, a known volume of both the organic and aqueous phase is collected via a filtered needle. Subsequently, the concentration of ON.1210.Na is determined by HPLC after adequate dilution.
  • the drug is dissolved in different pH buffers as outlined in Table 20.
  • One hundred mL of each solution is prepared in a volumetric flask. Each solution is filtered through a 0.22um filter. Approximately, four mL of the above solution is placed in 5 ml ampoules and sealed by a propane torch. The pH of the solution is determined at time zero and at each time interval. All the ampoules are placed in a 75 0 C constant temperature oven. Any color changes or precipitation in the solution during the sample collection is visually observed. Concentration of the drug is determined at time zero and other time intervals by HPLC. The sampling schedules for the stability data are shown in Table 21. The concentration of the drug at different time points is shown in Table 22. Thermal analyses
  • a differential scanning calorimeter (DSC) (model DSC-50, Shimadzu, Kyoto, Japan) and a thermogravimetric analyzer (TGA) (model TGA-50, Shimadzu, Kyoto, Japan) are connected to a thermal analysis operating system (TA-50WS, Shimadzu, Kyoto, Japan).
  • the heat of fusion is calibrated using indium (purity
  • the sample to be analyzed (5-10 mg) by DSC is crimped non-hermetically in an aluminum pan and heated from 30 to 400 0 C at a rate of 10°C/min under a stream of nitrogen (flow rate of 20 mL/min).
  • TGA thermogravimetric analysis
  • the ON.1210 free acid, sodium salt and the precipitate from filtered saturated solution of ON.1210.Na kept at refrigerated temperature are analyzed for its crystallinity by XRPD.
  • the instrument used is a Siemens D5OO5.
  • the samples are analyzed at room temperature with a scan range (2 ⁇ ) of 5° to 40° (Step scan, step size of 0.05°, dwell time of 1 second).
  • the sample holder is a Zero background holder.
  • the octanol-water partition coefficient of the drug is determined at 25 0 C using equal volumes (10 ml) of saturated solution of ON.1210.Na in n-octanol and HPLC water. Similarly, the partition coefficient is determined using simulated gastric and intestinal fluid without enzymes. The octanol-water partition coefficient is determined using the following equation: ConcentratioTi of drug in Octanol Phase
  • the octanol-water partition coefficient determined in triplicate samples is determined to be 1.28 to 2.87.
  • the pH of the aqueous phase is 8.1.
  • the partition coefficient using simulated gastric fluid can not be determined because of the extremely low solubility of ON.1210.Na at a pH of 8.1.
  • the pH of the simulated gastric fluid is 1.62.
  • the partition coefficient using simulated intestinal fluid is 0.74 to 2.1.
  • the data obtained from partition coefficient determination is found to be highly variable. Hence, further investigation is necessary to identify this variability.
  • the pH of the simulated intestinal fluid is 7.83.
  • the solubility of the ON,1210.Na salt is tested in a Mcllvaine type buffer with 0.1M ionic strength.
  • the buffers are prepared using the recipe mentioned in Table 16 using various volumes of 0.15 M citric acid monohydrate, and 0.2 M sodium phosphate dibasic, 12 hydrate.
  • the final pH is adjusted using 0.1N sodium hydroxide or 0. IN hydrochloric acid until the pH is within ⁇ 0.1 pH units of the target pH.
  • the solutions are then protected from light, and placed on a shaker.
  • the solutions are agitated for 24 to 96 hours at ambient conditions.
  • the vials are then removed from the orbital shaker, and the final pH of the solutions is measured for each sample.
  • the solutions are then filtered, and analyzed by HPLC.
  • the pH solubility data is shown in Table 18 and the pH solubility profile is shown in Figure 11.
  • the pKa of the weakly acidic drug is determined from pH-solubility data using the equation provided below.
  • the intrinsic solubility is taken as 0.000154mg/mL in this case.
  • the pKa determined by the saturated solubility study was 2.85 ⁇ 0.59.
  • the drug is dissolved in different pH buffers as outlined in Table 20.
  • One hundred mL of each solution is prepared in volumetric flask. Each solution is filtered through 0.22um filter. Approximately, four mL of the above solution is placed in 5 ml ampoules and sealed by a propane torch. The pH of the solution is determined at time zero and at each time interval. All the ampoules are placed in a 75 0 C constant temperature oven. Any color changes or precipitation in the solution during the sample collection is visually observed.
  • Concentration of the drug is determined at time zero and other time intervals by HPLC. The sampling schedules for the stability data are shown in Table 21. The pH and drug content of each sample are determined. The concentration at each time point and their pH is provided in Table 22. Table 20. Concentration of the drug used for the pH stability studies at 75 0 C
  • the degradation of ON.1210.Na seems to follow a pseudo first order reaction.
  • the rate constant for the degradation is determined using a linear regression at each individual pH.
  • the apparent first order rate constant as a function of pH are listed in Table 23.
  • the stability of ON.1210.Na in the solid state is determined by exposing the drug at 75°C over a prolonged time.
  • the sample is crimped in a 10 mL injection vial and kept at the above temperature.
  • the sample is collected after 15 days and one month and reconstituted with diluting solution and its concentration is determined by HPLC. Appearance of any additional peak in the chromatogram is also noted.
  • a control sample is represented by ON.1210.Na not exposed to 75°C and reconstituted to a known concentration with diluting solution. The results of this study are depicted in Table 24.
  • the solid state stability data shows that there is a slight increase in potency of the compound as a function of time at 75 0 C. This is probably due to the loss of moisture present in the sample. This was confirmed by determining the moisture content of the bulk ON.1210.Na. The result shows that there is about 14.5% of moisture in the sample which equates to 3 moles of water per mole of ON.1210.Na. The chromatograms showed no evidence of degradation of the sample.
  • a differential scanning calorimeter (DSC) (model DSC-50, Shimadzu, Kyoto, Japan) and a thermogravimetric analyzer (TGA) (model TGA-50, Shimadzu, Kyoto, Japan) are connected to a thermal analysis operating system (TA-50WS, Shimadzu, Kyoto, Japan).
  • the heat of fusion is calibrated using indium (purity 99.99%; mp 156.4; ⁇ H 6.8 mcal/mg).
  • the sample to be analyzed (5-10 mg) by DSC is crimped nonhermetically in an aluminum pan and heated from 30 to 400 0 C at a rate of 10°C/min under a stream of nitrogen (flow rate of 20 mL/min).
  • thermogravimetric analysis TGA
  • approximately 10 mg of the sample is weighed into aluminum pans and heated from 30 to 400 0 C at a heating rate of 10°C/min under nitrogen purge.
  • the DSC thermogram indicates two thermal events: (i) an endothermic peak at 5O 0 C possible due to desolvation or dehydration. This is further supported by the TGA thermogram which also indicates a weight loss exactly at the same temperature range, and (ii) the exothermic peak at 360 0 C probably due to the melting of the drug with decomposition.
  • the samples free acid (ON.1210), the salt (ON.1210.Na) and the precipitated sample from filtered saturated ON.1210.Na solution kept at refrigerated condition are analyzed using Siemens powder X Ray diffractometer under ambient conditions.
  • the scan range (2 ⁇ ) is from 5° to 40° (Step scan, step size of 0.05°, with a dwell time of 1 second).
  • the results are shown in Figures 14-15, along with the peak search report.
  • Figures 15 clearly shows that the sodium salt of ON.1210 is a crystalline material.
  • the sodium salt has a tendency to form a supersaturated solution in water, Upon storage, the solution starts showing some precipitate.
  • the precipitate is isolated, dried and characterized by HPLC, DSC, TGA and XRPD.
  • the precipitate is dissolved in acetonitrile water mixture and analyzed by HPLC.
  • the precipitate elutes at the same time as the standard of ON.1210.Na suggesting that the precipitate is of ON.1210.
  • the precipitate is further characterized by DSC.
  • a thermogram of the precipitate does not show the transition around 5O 0 C as is seen with the ON.1210.Na standard. However, it does show the same melting / decomposition around 36O 0 C.
  • the precipitate is further characterized by XRPD.
  • the diffractogram shows most of the peaks that are observed with ON.1210.Na except the one observed at 8.815.
  • Table 27 Peak search report of precipitated sample
  • this drug e.g., ON.1210.Na
  • ON.1210.Na is surprisingly demonstrated to be quite stable in an aqueous environment at biological pH. Therefore, it can be formulated as an efficacious shelf stable parenteral formulation.
  • the aqueous solubility of the drug is low and can be enhanced by increased pH, cosolvents and, by formation of inclusion complex.
  • Related compounds include, but are not limited to (Z)-4-chlorostyryl-4- chlorobenzylsulfone; (Z)-4-chlorostyryl-4-fluorobenzylsulfone; (Z)-4-fluorostyryl- 4-chlorobenzylsulfone; (Z)-4-bromostyryl-4-chlorobenzylsulfone; and (Z)-4- bromostyryl-4-fluorobenzylsulfone.
  • HFL-I cells which are normal diploid lung fibroblasts, were plated into 24 well dishes at a cell density of 3000 cells per 10 mm 2 in DMEM completed with 10% fetal bovine serum and antibiotics.
  • the test compounds listed in Table 28 were added to the cells 24 hours later in select concentrations from 2.5 to 20 micromolar, inclusive, using DMSO as a solvent.
  • Control cells were treated with DMSO alone.
  • the cells were exposed to the test compound or DMSO for 24 hrs.
  • the cells were then irradiated with either 10 Gy (gray) or 15 Gy of ionizing radiation (IR) using a JX. Shepherd Mark I, Model 30-1 Irradiator equipped with 137 cesium as a source.
  • the medium on the test and control cells was removed and replaced with fresh growth medium without the test compounds or DMSO.
  • the irradiated cells were incubated for 96 hours and duplicate wells were trypsinized and replated onto 100 mm 2 tissue culture dishes.
  • the replated cells were grown under normal conditions with one change of fresh medium for 3 weeks. The number of colonies from each 100 mm 2 culture dish, which represents the number of surviving cells, was determined by staining the dishes as described below.
  • the medium was removed and the plates were washed one time with room temperature phosphate buffered saline.
  • the cells were stained with a 1:10 diluted Modified Giemsa staining solution (Sigma) for 20 minutes. The stain was removed, and the plates were washed with tap water. The plates were air dried, the number of colonies from each plate were counted and the average from duplicate plates was determined.
  • mice age 10-12 weeks were divided into two treatment groups of 10 mice each.
  • One group designated the "200x2" group, received intraperitoneal injections of 200 micrograms (E)-4-carboxystyryl-4- chlorobenzylsulfone dissolved in DMSO (a 10 mg/Kg dose, based on 20 g mice) 18 and 6 hours before irradiation with 8 Gy gamma radiation.
  • the other group received intraperitoneal injections of 500 micrograms (E)-4- carboxystyryl-4-chlorobenzylsulfone dissolved in DMSO (a 25 mg/Kg dose, based on 20 g mice) 18 and 6 hours before irradiation with 8 Gy gamma radiation.
  • a control group of 16 animals received 8 Gy gamma radiation alone.
  • Mortality of control and experimental groups was assessed for 40 days after irradiation, and the results are shown in FIG.5. By day 20 post-irradiation, the control mice exhibited a maximum mortality rate of 80%; the 8 Gy dose of gamma radiation is thus considered an LD 8O dose.
  • mice age 10-12 weeks were divided into two treatment groups of 10 and 9 mice, respectively.
  • One group designated the "200x2" group, received intraperitoneal injections of 200 micrograms (E)-4-carboxystyryl-4- chlorobenzylsulfone dissolved in DMSO (a 10 mg/Kg dose, assuming 20 g mice) 18 and 6 hours before irradiation with 8 Gy gamma radiation.
  • the other group designated "200 Post," received an intraperitoneal injection of 200 micrograms (E)- 4-carboxystyryl-4-chlorobenzylsulfone dissolved in DMSO (a 10 mg/Kg dose, based on 20 g mice) 15 minutes after irradiation with 8 Gy gamma radiation.
  • a control group of 16 animals received 8 Gy gamma radiation alone. Mortality of control and experimental groups was assessed for 40 days after irradiation, and the results are shown in FIG.6.
  • FIG.6 shows that treatment of mice with (E)-4-carboxystyryl-4- chlorobenzylsulfone after irradiation resulted in significant delay in radiation- induced mortality as compared with the control animals. While the radioprotection afforded by post-irradiation treatment is not as great as seen with pre-irradiation treatment, (E)-4-carboxystyryl-4-chlorobenzylsulfone is nonetheless effective in mitigating the effects of radiation toxicity after the subject has received the radiation dose.

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Abstract

L'invention concerne une composition pharmaceutique destinée à être administrée avant ou après avoir été exposée à un rayonnement d'ionisation afin de réduire les effets toxiques du rayonnement chez un sujet. Une quantité efficace de la composition pharmaceutique selon l'invention comprend une quantité efficace d'au moins une formulation d'aryl sulfones non saturés a, ß radioprotecteurs et d'au moins un composant choisi dans le groupe constitué de a) au moins un polymère hydrosoluble dans une quantité comprise entre environ 0,5 % et environ 90 % en poids, b) au moins une cyclodextrine chimiquement modifiée dans une quantité comprise entre environ 20 % et environ 60 % en poids et c) du DMA dans une quantité comprise entre environ 10 % et environ 50 % en poids.
PCT/US2006/029109 2005-07-29 2006-07-28 Formulation d'aryl sulfones non satures ?, ? radioprotecteurs Ceased WO2007016201A2 (fr)

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CA2617147A CA2617147C (fr) 2005-07-29 2006-07-28 Formulation d'aryl sulfones non satures .alpha.,.beta. radioprotecteurs
EP06788612A EP1909775B1 (fr) 2005-07-29 2006-07-28 Formulation d'aryl sulfones non satures alpha, beta radioprotecteurs
US11/989,468 US20110028504A1 (en) 2005-07-29 2006-07-28 Formulation of radioprotective alpha beta unsaturated aryl sulfones
JP2008524129A JP5107246B2 (ja) 2005-07-29 2006-07-28 放射線防護α，β−不飽和アリールスルホンの製剤
KR1020087004185A KR101309903B1 (ko) 2005-07-29 2006-07-28 방사선 보호 α,β 불포화 아릴설폰 제형
NZ565561A NZ565561A (en) 2005-07-29 2006-07-28 Formulation of radioprotective alpha, beta unsaturated aryl sulfones
AU2006275822A AU2006275822B2 (en) 2005-07-29 2006-07-28 Formulation of radioprotective alpha, beta unsaturated aryl sulfones
IL189063A IL189063A (en) 2006-07-28 2008-01-28 Pharmaceutical preparation to reduce the toxic effect of ionizing radiation containing carbostyril - chlorobenzylsulfon, cyclodexrin adapted, water-soluble polymer and n, n - dimethylacetamide

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WO2011119863A1 (fr) 2010-03-26 2011-09-29 Onconova Therapeutics, Inc. Formule aqueuse stable améliorée de (e)-4-carboxystyryl-4-chlorobenzyl sulfone
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CN104320971A (zh) * 2010-03-24 2015-01-28 安哥洛华治疗公司 用于预防和治疗创伤的组合物和方法
CN106432011A (zh) * 2016-09-18 2017-02-22 中国医学科学院放射医学研究所 一类具有辐射防护作用的新化合物、其制备方法及其药物应用

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WO2018071448A1 (fr) 2016-10-11 2018-04-19 The Regents Of The University Of California Systèmes et procédés d'encapsulation et de conservation de matière organique pour analyse

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US8063109B2 (en) 2004-07-19 2011-11-22 Onconova Therapeutics, Inc. Formulations for parenteral administration of (e)-2, 6-dialkoxystyryl 4-substituted benzylsulfones
EP2046343A4 (fr) * 2006-07-28 2009-11-25 Onconova Therapeutics Inc Formulations d'arylsulfones alpha, beta -insaturées radioprotectrices
KR101156325B1 (ko) * 2006-07-28 2012-07-10 온코노바 테라퓨틱스, 인코포레이티드 방사선 보호 α,β 불포화 아릴설폰 제형
EP2769719A1 (fr) * 2006-07-28 2014-08-27 Onconova Therapeutics, Inc. Formulations de radioprotecteurs alpha, beta insaturé sulfones d'aryle
JP2012511931A (ja) * 2008-12-16 2012-05-31 オンコノバ・セラピューティックス・インコーポレーテッド ヒトにおける細胞毒性物質の有害作用に対する治療レジメンの有効性を決定する方法
CN104320971A (zh) * 2010-03-24 2015-01-28 安哥洛华治疗公司 用于预防和治疗创伤的组合物和方法
WO2011119863A1 (fr) 2010-03-26 2011-09-29 Onconova Therapeutics, Inc. Formule aqueuse stable améliorée de (e)-4-carboxystyryl-4-chlorobenzyl sulfone
US9060967B2 (en) 2010-03-26 2015-06-23 Onconova Therapeutics, Inc Stable aqueous formulation of (E)-4-carboxystyryl-4-chlorobenzyl sulfone
CN106432011A (zh) * 2016-09-18 2017-02-22 中国医学科学院放射医学研究所 一类具有辐射防护作用的新化合物、其制备方法及其药物应用

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JP2009502943A (ja) 2009-01-29
EP1909775B1 (fr) 2012-05-16
AU2006275822B2 (en) 2012-02-02
EP1909775A2 (fr) 2008-04-16
AU2006275822A1 (en) 2007-02-08
NZ565561A (en) 2011-01-28
KR101309903B1 (ko) 2013-09-17
WO2007016201A3 (fr) 2009-04-16
KR20080046164A (ko) 2008-05-26
JP5107246B2 (ja) 2012-12-26
CA2617147A1 (fr) 2007-02-08
CA2617147C (fr) 2014-01-21
US20110028504A1 (en) 2011-02-03

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